Impeding platinum-based chemotherapeutic induced ototoxicity using a colony stimulating factor 1 receptor inhibitor

Abstract

Disclosed is a method of impeding platinum-based chemotherapeutic induced ototoxicity, and/or other toxicity, the method comprising administering a colony stimulating factor 1 receptor (CSF1R) inhibitor to a subject in an amount sufficient to impede ototoxicity, and/or other toxicity, inducible by a platinum-based chemotherapeutic; and administering the platinum-based chemotherapeutic to the subject. The CSF1R inhibitor can be, for example, pexidartinib. The platinum-based chemotherapeutic can be, for example, cisplatin. Compositions, medicaments, kits, and uses are disclosed related to the same. Further, a method of screening for a compound able to impede a platinum-based chemotherapeutic induced toxicity is disclosed.

What is claimed is: 
     
         1 . A method of impeding platinum-based chemotherapeutic induced ototoxicity, the method comprising:
 administering a colony stimulating factor  1  receptor (CSF1R) inhibitor to a subject in an amount sufficient to impede ototoxicity inducible by a platinum-based chemotherapeutic; and   administering the platinum-based chemotherapeutic to the subject;   optionally diagnosing the subject with cancer; and   optionally administering radiation to the subject, or administering at least one non-platinum-based chemotherapeutic to the subject, or both;   wherein optionally the CSF1R inhibitor comprises pexidartinib, a prodrug thereof, or a salt thereof, or any combination thereof;   wherein optionally the platinum-based chemotherapeutic comprises cisplatin; and   wherein optionally the ototoxicity comprises hearing loss.   
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein optionally the subject has been diagnosed with a cancer-prior to the administering of the colony stimulating factor  1  receptor (CSF1R);
 wherein optionally the subject is diagnosed with cancer after the administering of the platinum-based chemotherapeutic; 
 wherein optionally the cancer comprises testicular cancer, a bladder cancer, a lung cancer, a stomach cancer, a head & neck cancer, an ovarian cancer, a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma, or any combination thereof; 
 wherein optionally the cancer comprises a solid tumor or a liquid tumor; 
 wherein optionally the cancer is metastatic; 
 wherein optionally the cancer excludes a tenosynovial giant cell tumor (TGCT). 
 
     
     
         5 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the CSF1R inhibitor comprises a small molecule therapeutic, a biologic, a prodrug thereof, or a salt thereof, or any combination thereof;
 wherein optionally the salt is a pharmaceutically acceptable salt;   wherein optionally the salt comprises a hydrochloride salt;   wherein optionally the salt comprises a monohydrochloride salt, or a dihydrochloride salt, or both;   wherein optionally the salt is a monohydroxychloride salt.   
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein the CSF1R inhibitor comprises a tyrosine kinase inhibitor;
 wherein optionally the CSF1R inhibitor comprises pexidartinib, edicotinib PLX647, sotuletinib, vimseltinib, or imatinib, a prodrug thereof, or a salt thereof, or any combination thereof.   
     
     
         15 - 22 . (canceled) 
     
     
         23 . The method of  claim 12 , wherein the CSF1R inhibitor comprises an antibody or antigen-binding fragment thereof;
 wherein optionally the CSF1R inhibitor comprises a monoclonal antibody;   wherein optionally the CSF1R inhibitor comprises a chimeric antibody;   wherein optionally the CSF1R inhibitor comprises a humanized antibody;   wherein optionally the CSF1R inhibitor comprises cabiralizumab, LY3022855, emactuzumab, axatilimab, AMG820, a prodrug thereof, or a salt thereof, or any combination thereof.   
     
     
         24 - 28 . (canceled) 
     
     
         29 . The method of  claim 12 , wherein the CSF1R inhibitor comprises an inhibitor selective to CSF1R relative to proto-oncogene receptor kinase (c-KIT), or FMS-like tyrosine kinase 3 with internal tandem duplication mutation (FLT3-ITD), or both. 
     
     
         30 . The method of  claim 12 , wherein the CSF1R inhibitor comprises a reversible inhibitor, or an irreversible inhibitor, or both;
 wherein optionally the CSF1R inhibitor comprises a competitive inhibitor, or a non-competitive inhibitor, or both;   wherein optionally the CSF1R inhibitor antagonizes binding to CSF1R, or signaling through CSF1R, or both of CSF1, or IL-34, or both.   
     
     
         31 - 32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein the platinum-based chemotherapeutic comprises a chemotherapeutic capable of forming a covalent adduct with DNA of the subject;
 wherein optionally the platinum-based chemotherapeutic comprises cisplatin, carboplatin, oxaliplatin, paraplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, a prodrug thereof, or a salt thereof, or any combination thereof;   wherein optionally the platinum-based chemotherapeutic is administered from one time to ten times subsequent to administration of the CSF1R inhibitor;   wherein optionally the platinum-based chemotherapeutic is administered at least three times subsequent to administration of the CSF1R inhibitor.   
     
     
         34 - 37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein the ototoxicity comprises hearing loss, loss of balance, or tinnitus, or any combination thereof;
 wherein optionally the hearing loss comprises sensorineural hearing loss, bilateral hearing loss, progressive hearing loss, irreversible hearing loss, or high frequency hearing loss, or any combination thereof;   wherein optionally the ototoxicity comprises mechanosensory inner ear hair cell toxicity:   wherein optionally the hearing loss is associated with a threshold shift in auditory brainstem response (ABR);   wherein optionally the hearing loss is associated with a decrease in amplitude of distortion product otoacoustic emissions (DPOAE); or   wherein optionally the mechanosensory inner ear hair cell comprises an inner hair cell, or an outer hair cell, or both.   
     
     
         39 - 45 . (canceled) 
     
     
         46 . The method of  claim 12 , wherein the CSF1R inhibitor inhibits macrophages, or microglia, or both;
 wherein optionally the macrophages comprise cochlear resident macrophages, or recruited macrophages, or both;   wherein optionally the resident macrophages comprise perivascular resident macrophage-like melanocytes (PVM/Ms);   wherein optionally the CSF1R inhibitor affects the blood labyrinth barrier (BLB);   wherein optionally the CSF1R inhibitor inhibits proto-oncogene receptor kinase (c-KIT), or FMS-like tyrosine kinase 3 with internal tandem duplication mutation (FLT3-ITD), or both; or   wherein optionally a c-KIT inhibitor, a FLT3-ITD inhibitor, or both are administered in addition to the CSF1R inhibitor.   
     
     
         47 - 50 . (canceled) 
     
     
         51 . The method of  claim 1 , further comprising testing the hearing of the subject;
 wherein optionally testing the hearing of the subject is performed before administering the platinum-based chemotherapeutic, or after administering the platinum-based chemotherapeutic, or both;   wherein optionally testing the hearing of the subject comprises testing for threshold shifts in auditory brainstem responses (ABR), or amplitude of distortion product-otoacoustic emissions (DPOAE), or both.   
     
     
         52 - 53 . (canceled) 
     
     
         54 . The method of  claim 1 , wherein the amount of CSF1R inhibitor administered is sufficient to impede weight loss inducible by the platinum-based chemotherapeutic, impede inner ear hair loss inducible by the platinum-based chemotherapeutic, impede outer hair dysfunction inducible by the platinum-based chemotherapeutic, impede entry of cisplatin into the inner ear, impede hematological toxicity induced by the platinum-based chemotherapeutic, or any combination thereof;
 wherein optionally the hematological toxicity comprises myelosuppression.   
     
     
         55 . (canceled) 
     
     
         56 . The method of  claim 1 , wherein the CSF1R inhibitor is administered before, during, or after, or any combination thereof, administration of the platinum-based chemotherapeutic;
 wherein optionally the CSF1R inhibitor is administered before one to ten administrations of the platinum-based chemotherapeutic;   wherein optionally the CSF1R inhibitor is administered at from about 0.5 mg to about 500 mg per dose;   wherein optionally the CSF1R inhibitor is administered in solid dosage form; or   wherein optionally the CSF1R inhibitor and platinum-based chemotherapeutic are administered in admixture.   
     
     
         57 - 62 . (canceled) 
     
     
         63 . The method of  claim 1 , wherein the platinum-based chemotherapeutic is administered at from about 0.5 mg to about 500 mg per dose;
 wherein optionally the platinum-based chemotherapeutic is administered intravenously;   wherein optionally the CSF1R inhibitor and platinum-based chemotherapeutic are administered in admixture.   
     
     
         64 - 65 . (canceled) 
     
     
         66 . The method of  claim 1 , wherein the subject is a mammal;
 wherein optionally the subject is a rodent or a primate;   wherein optionally the subject is a companion animal;   wherein optionally the subject is a human;   wherein optionally the subject is a juvenile;   wherein optionally the subject is an adult.   
     
     
         67 - 72 . (canceled) 
     
     
         73 . A pharmaceutical composition comprising the CSF1R inhibitor, the platinum-based therapeutic, and a pharmaceutically acceptable excipient. 
     
     
         74 . A kit comprising the CSF1R inhibitor and the platinum-based chemotherapeutic. 
     
     
         75 . A method of screening for a compound able to impede a platinum-based chemotherapeutic induced toxicity, the method comprising:
 measuring a physiologic parameter in a non-human subject to obtain a first measurement, the physiological parameter associated with the toxicity and deleteriously affected by a platinum-based chemotherapeutic;   administering a test compound to the non-human subject after measuring the physiologic parameter;   administering the platinum-based chemotherapeutic to the non-human subject after measuring the physiologic parameter;   measuring the physiologic parameter in the non-human subject subsequent to administration of the test compound and the platinum-based chemotherapeutic to obtain a second measurement; and   comparing the first and second measurements, a smaller deleterious change, than that experienced by a non-human subject not administered the test compound, indicating the test compound as a therapeutic capable of impeding the toxicity;   wherein optionally the toxicity is an ototoxicity.   
     
     
         76 - 77 . (canceled) 
     
     
         78 . A colony stimulating factor 1 receptor (CSF1R) inhibitor for use in impeding ototoxicity inducible by a platinum-based chemotherapeutic. 
     
     
         79 . (canceled) 
     
     
         80 . Use of a colony stimulating factor 1 receptor (CSF1R) inhibitor A process for manufacture of a medicament comprising a colony stimulating factor 1 receptor (CSF1R) inhibitor to impede ototoxicity inducible by a platinum-based chemotherapeutic.